Download AP Biology - SPS186.org

Division Ave. High School
Ms. Foglia
AP Biology
Regulation of Cell Division
AP Biology
2008-2009
Coordination of cell division
§ A multicellular organism needs to
coordinate cell division across different
tissues & organs
u critical for normal growth,
development & maintenance
§ coordinate timing of
cell division
§ coordinate rates of
cell division
§ not all cells can have the
same cell cycle
AP Biology
Frequency of cell division
§
Frequency of cell division varies by cell type
u embryo
§ cell cycle < 20 minute
u
skin cells
§ divide frequently throughout life
§ 12-24 hours cycle
u
liver cells
§ retain ability to divide, but keep it in reserve M
metaphase anaphase
§ divide once every year or two
telophase
prophase
u
mature nerve cells & muscle cells
§ do not divide at all after maturity
§ permanently in G 0
S
G2
C
interphase (G1, S, G2 phases)
mitosis (M)
cytokinesis (C)
G1
AP Biology
1
Division Ave. High School
Ms. Foglia
AP Biology
There’s no
turning back,
now!
Overview of Cell Cycle Control
§ Two irreversible points in cell cycle
u
u
replication of genetic material
separation of sister chromatids
§ Checkpoints
u
process is assessed
& possibly halted
sister chromatids
ü
centromere
single-stranded
AP Biology
chromosomes
ü
double-stranded
chromosomes
Checkpoint control system
§ Checkpoints
cell cycle controlled by STOP & GO
chemical signals at critical points
u signals indicate if key cellular
processes have been
completed correctly
u
AP Biology
Checkpoint control system
§ 3 major checkpoints:
u
G1/S
u
G2/M
§ can DNA synthesis begin?
§ has DNA synthesis been
completed correctly?
§ commitment to mitosis
u
spindle checkpoint
§ are all chromosomes
attached to spindle?
§ can sister chromatids
separate correctly?
AP Biology
2
Division Ave. High School
Ms. Foglia
AP Biology
G 1/S checkpoint
§ G 1/S checkpoint is most critical
u
primary decision point
u
if cell receives “GO” signal, it divides
§ “restriction point”
§ internal signals: cell growth (size), cell nutrition
§ external signals: “growth factors”
if cell does not receive
signal, it exits cycle &
switches to G0 phase
u
§ non-dividing, working state
AP Biology
G 0 phase
§ G 0 phase
u
u
non-dividing, differentiated state
most human cells in G0 phase
§ liver cells
§ in G 0 , but can be
“called back” to cell
cycle by external cues
§ nerve & muscle cells
§ highly specialized
§ arrested in G 0 & can
never divide
AP Biology
Activation of cell division
§ How do cells know when to divide?
u
cell communication signals
§ chemical signals in cytoplasm give cue
§ signals usually mean proteins
w activators
w inhibitors
AP Biology
experimental evidence: Can you explain this?
3
Division Ave. High School
Ms. Foglia
AP Biology
“Go-ahead” signals
§ Protein signals that promote cell
growth & division
u internal signals
§ “promoting factors”
u
external signals
§ “growth factors”
§ Primary mechanism of control
u
phosphorylation
§ kinase enzymes
§ either activates or inactivates cell signals
AP Biology
inactivated Cdk
Cell cycle signals
§ Cell cycle controls
u cyclins
§ regulatory proteins
§ levels cycle in the cell
u Cdks
§ cyclin-dependent kinases
§ phosphorylates cellular proteins
w activates or inactivates proteins
u
activated Cdk
Cdk-cyclin complex
§ triggers passage through different stages
of cell cycle
AP Biology
Cyclins & Cdks
1970s-80s | 2001
§ Interaction of Cdk’s & different cyclins triggers the
stages of the cell cycle
AP Biology
Leland H. Hartwell
checkpoints
Tim Hunt
Cdks
Sir Paul Nurse
cyclins
4
Division Ave. High School
Ms. Foglia
AP Biology
Spindle checkpoint
G2 / M checkpoint
Chromosomes attached
at metaphase plate
• Replication completed
• DNA integrity
Active
Inactive
Inactive
Cdk / G2
M
cyclin (MPF)
Active
APC
cytokinesis
C
mitosis
G2
G1
S
MPF = Mitosis
Promoting Factor
APC = Anaphase
AP BiologyComplex
Promoting
Cdk / G1
cyclin
Active
G1 / S checkpoint
Inactive
• Growth factors
• Nutritional state of cell
• Size of cell
Cyclin & Cyclin-dependent kinases
§ CDKs & cyclin drive cell from
one phase to next in cell cycle
proper regulation of cell
cycle is so key to life
that the genes for these
regulatory proteins
have been highly
conserved through
evolution
u the genes are basically
the same in yeast,
insects, plants &
animals (including
humans)
u
AP Biology
External signals
§
Growth factors
u coordination between cells
u protein signals released by
body cells that stimulate other
cells to divide
§ density-dependent inhibition
AP Biology
w crowded cells stop dividing
w each cell binds a bit of growth
factor
n not enough activator left to
trigger division in any one cell
§ anchorage dependence
w to divide cells must be attached to a
substrate
n “touch sensor” receptors
5
Division Ave. High School
Ms. Foglia
AP Biology
Growth factor signals
growth factor
nuclear pore
nuclear membrane
P
cell division
P
cell surface
receptor
protein kinase
cascade
Cdk
P
E2F
P
chromosome
P
APcytoplasm
Biology
nucleus
Example of a Growth Factor
§
Platelet Derived Growth Factor (PDGF)
u made by platelets in blood clots
u binding of PDGF to cell receptors stimulates
cell division in connective tissue
§ heal wounds
Don’t forget
to mention
erythropoietin!
(EPO)
AP Biology
Growth Factors and Cancer
§ Growth factors can create cancers
u
proto-oncogenes
§ normally activates cell division
w growth factor genes
w become oncogenes (cancer-causing) when mutated
§ if switched “ON” can cause cancer
§ example: RAS (activates cyclins)
u
tumor-suppressor genes
§ normally inhibits cell division
§ if switched “OFF” can cause cancer
§ example: p53
AP Biology
6
Division Ave. High School
Ms. Foglia
AP Biology
Cancer & Cell Growth
§
§
Cancer is essentially a failure
of cell division control
u unrestrained, uncontrolled cell growth
What control is lost?
u lose checkpoint stops
u gene p53 plays a key role in G1/S restriction point
p53 is the
Cell Cycle
Enforcer
§ p53 protein halts cell division if it detects damaged DNA
w options:
n stimulates repair enzymes to fix DNA
n forces cell into G0 resting stage
n keeps cell in G1 arrest
n causes apoptosis of damaged cell
§ ALL cancers have to shut down p53 activity
AP Biology
p53 discovered at Stony Brook by Dr. Arnold Levine
p53 — master regulator gene
NORMAL p53
p53 allows cells
with repaired
DNA to divide.
p53
protein
DNA repair enzym e
p53
protein
Step 1
Step 2
Step 3
DNA dam age is caused
by heat, radiation, or
chem icals.
Cell division stops, and
p53 triggers enzym es to
repair dam aged region.
p53 triggers the destruction
of cells dam aged beyond repair.
ABNORMAL p53
abnorm al
p53 protein
Step 1
Step 2
DNA dam age is
caused by heat,
radiation, or
chem icals.
The p53 protein fails to stop
cell division and repair DNA.
Cell divides without repair to
dam aged DNA.
AP Biology
cancer
cell
Step 3
Dam aged cells continue to divide.
If other dam age accum ulates, the
cell can turn cancerous.
Development of Cancer
§
Cancer develops only after a cell experiences
~6 key mutations (“hits”)
u unlimited growth
§ turn on growth promoter genes
u
ignore checkpoints
u
escape apoptosis
u
immortality = unlimited divisions
u
promotes blood vessel growth
u
overcome anchor & density dependence
§ turn off tumor suppressor genes (p53)
It’s like an
out-of-control
car with many
§ turn on chromosome maintenance genes systems failing!
§ turn off suicide genes
§ turn on blood vessel growth genes
AP Biology
§ turn off touch-sensor gene
7
Division Ave. High School
Ms. Foglia
AP Biology
What causes these “hits”?
§ Mutations in cells can be triggered by
UV radiation
chemical exposure
u radiation exposure
u heat
cigarette smoke
pollution
u age
u genetics
u
u
u
u
AP Biology
Tumors
§ Mass of abnormal cells
u
Benign tumor
§ abnormal cells remain at original site as a
lump
w p53 has halted cell divisions
§ most do not cause serious problems &
can be removed by surgery
u
AP Biology
Malignant tumor
§ cells leave original site
w lose attachment to nearby cells
w carried by blood & lymph system to other tissues
w start more tumors = metastasis
§ impair functions of organs throughout body
Traditional treatments for cancers
§ Treatments target rapidly dividing
cells
u high-energy radiation
§ kills rapidly dividing cells
u chemotherapy
§ stop DNA replication
§ stop mitosis & cytokinesis
§ stop blood vessel growth
AP Biology
8
Division Ave. High School
Ms. Foglia
AP Biology
New “miracle drugs”
§ Drugs targeting proteins (enzymes) found
only in cancer cells
u Gleevec
§ treatment for adult leukemia (CML)
& stomach cancer (GIST)
§ 1st successful drug targeting only cancer cells
without
Gleevec
with
Gleevec
Novartes
AP Biology
9